Abstract 1232: Xerna࣪ TME Panel: A pan-cancer RNA-based investigational assay designed to predict patient responses to angiogenic and immune targeted therapies
Authors: Seema Iyer, Luka Ausec, Daniel Pointing, Matjaz Zganec, Robert Cvitkovic, Miha Stajdohar, Valerie Chamberlain Santos, Kerry Culm, Mokenge Malafa, Jeeyun Lee, Rafael Rosengarten, Laura Benjamin, Mark T. Uhlik
Journal: Cancer Research (2022)

Abstract While numerous anti-angiogenic and immune targeting therapies have become standard-of-care treatments for oncology, predictive biomarkers for these agents have been either entirely lacking or challenged by inconsistencies across indications. We have developed and validated the Xerna TME Panel as a novel machine learning-based RNA-sequencing biomarker assay that guides patient selection for tumor microenvironment (TME)-targeted therapies across multiple tumor types. Gene expression data sets from both public sources and clinical practice representing over 5000 samples across 7 different tumor types were analyzed using the Xerna TME Panel. The Xerna TME Panel consists of an artificial neural net that learns complex gene expression interactions between angiogenesis and tumor immune biologies and robustly classifies patient samples into one of four TME biomarker subtypes: Angiogenesis (A), Immune Suppressed (IS), Immune Active (IA), or Immune Desert (ID). The vast majority (&amp;gt;75%) of all samples were assigned a TME class designation with confidence scores in the upper quartile and had nearly bimodal distributions for biomarker-positive versus -negative classifications. When compared to other independent gene signatures, such as those describing angiogenesis/mesenchymal biology, inflammation, and immune suppression, the expression profiles from the Xerna TME subtypes showed enrichment of those biological processes. Each TME subtype represented between ~15-40% of subjects of each tumor type, indicating balanced representation of subgroups within the patient populations. The Xerna TME designations were prognostic across tumor types, with “A” tumors generally associated with the worst survival and “IA” tumors associated with the best survival. The predictive ability of the Xerna TME Panel to enrich for tumor responses to targeted therapies in gastric cancer was also evaluated. In a ramucirumab+paclitaxel clinical cohort, the Xerna TME Panel high Angiogenesis score tumors (A and IS) demonstrated a 48% response rate compared to a 31% for low Angiogenesis score tumors (IA and ID). In an immune checkpoint inhibitor (ICI) cohort, high Immune score tumors (IA and IS) showed a response rate of 34% vs. 5% for low Immune score tumors (A and ID). Within the microsatellite stable patients (MSS), which historically have low response rates to ICIs, the Xerna TME Panel was able to enrich for responses between Immune high vs. Immune low score patients (25% vs. 3%). Currently in use to prospectively enroll patients into a Phase 3 ovarian cancer clinical trial and in development as a companion diagnostic (CDx) assay, the Xerna TME Panel is a robust, pan-cancer biomarker assay capable of characterizing TME dominant biologies to further advance the matching of patients with targeted therapeutics. Citation Format: Seema Iyer, Luka Ausec, Daniel Pointing, Matjaz Zganec, Robert Cvitkovic, Miha Stajdohar, Valerie Chamberlain Santos, Kerry Culm, Mokenge Malafa, Jeeyun Lee, Rafael Rosengarten, Laura Benjamin, Mark T. Uhlik. Xerna࣪ TME Panel: A pan-cancer RNA-based investigational assay designed to predict patient responses to angiogenic and immune targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1232.